Conjugates for the treatment of mesothelioma

Abstract

The present invention provides conjugates of cytokines and targeting peptides that is able to bind to a receptor expressed on tumor-associated vessels or to a component of the extracellular matrix associated to the tumor vessels, for treatment of malignant pleural mesothelioma. In particular, the invention provides conjugates comprising the cytokine TNF linked to a peptide containing the NGR motif. The invention further provides pharmaceutical compositions comprising such conjugate and pharmaceutical formulations comprising conjugates dissolved in appropriate buffers.

Description

FIELD OF THE INVENTION[0001]The present invention relates to cancer therapy, particularly, to the use of conjugates of cytokines and targeting peptides for the treatment of Malignant Pleural Mesothelioma (MPM). More particularly, the invention relates to the use of a conjugate comprising a peptide containing NGR motif and TNF (NGR-TNF) for the treatment of MPM.BACKGROUND[0002]Malignant pleural mesothelioma (MPM) is a rare aggressive neoplasm that arise primarily from the surface serosal cells of the pleural cavities, generally associated to a poor prognosis. The incidence of MPM is increasing throughout the world, and it is expected to rise in the next 10-20 years because of the increasing exposure to asbestos in past years.[0003]There is no standard of care for the treatment of MPM, and only a minority of patients are eligible for any potentially curative therapy. Complications of cytotoxic chemotherapy strongly influence physician decisions in the treatment of older (65 years of a...

AI Technical Summary

Benefits of technology

[0026]After the end of the study, the overall results obtained by treating 57 patients has shown that NGR-hTNF doubled the progression free survival observed with best supportive care that is the reference treatment for this patient population lacking a standard therapy. In addition, the results obtained with NGR-hTNF in terms of progression free survival are comparable with those obtained with combination therapies, such as gemcitabine plus vinorelbine or bevacizumab plus erlotinib with the advantage of administering only one drug that does not have the toxicities associated with those drugs.

[0027]Such data show that conjugates of cytokines and targeting peptides can be successfully used for the treatment of mesothelioma, even as second line treatment of patients refractory or resistant to chemotherapy regimen, that means effective even in a more resistant tumor than it was at first presentation and treatment.

[0028]Furthermore, low dose admi

Problems solved by technology

Single modality therapies (surgery, radiotherapy and chemotherapy) have failed to prolong patient survival.

However, this chemotherapeutic approach achieved only a modest increase in terms of progression-free (5.7 versus 3.9 months) and overall survival (12.1 versus 9.3 months) in comparison with cisplatin monochemotherapy.

Moreover, this chemotherapy combination even if performed in selected patient population (median age 60 years old, Karnofsky performance status at least of 70, that identifies a patient that cares for self and is unable to carry on normal activity or to do active work; or even greater performance status) was unexpectedly toxic and resulted in several treatment related deaths.

At the present time, several biological agents have been evaluated in phase II clinical trials but none resulted to be effective, even if tested in front line and in combination therapy, showing in some circumstances, an unsafe toxicity pattern.

Likewise, Imatinib (Glivec®), a 2-phenylaminopyrimidine tyrosine kinase inhibitor known to affect both c-Kit and PDGF alpha and beta receptors and approved for the treatment of chronic myeloid leukaemia, didn't show to be effective as front-line single-agent therapy in terms of time to tumo